ADMIRAL TRIAL

The ADMIRAL Trial Is a Phase 3 Study of the Only FDA-Approved Treatment in Relapsed or Refractory FLT3m+ AML^1-3

XOSPATA—an oral monotherapy FLT3-ITD and -TKD inhibitor—was evaluated in a Phase 3, open-label, multicenter, randomized clinical trial compared with a prespecified salvage chemotherapy in adult patients with relapsed or refractory FLT3m+ AML.^1,2

ADMIRAL study design^1,2

Randomization was stratified by patient response to first-line AML treatment and prespecified chemotherapy.^§ Prespecified chemotherapy regimens included¹:
- High-intensity combination regimens MEC^|| and FLAG-IDA^¶
- Low-intensity regimens LDAC^# and AZA**
The efficacy of XOSPATA was based on an interim analysis and a final analysis^1,2:
- CR/CRh was evaluated in an interim analysis in the XOSPATA arm only (n=138) and was summarized in the final analysis for both treatment groups^1,2
- The final analysis evaluated OS with XOSPATA vs salvage chemotherapy¹

*XOSPATA was given orally at a starting dose of 120 mg daily until unacceptable toxicity or lack of clinical benefit.¹

^†Patients in the ADMIRAL trial were eligible for HSCT. Patients who went on to receive transplant during the study had achieved a response in either treatment arm that allowed them to undergo HSCT based on each institution's assessment, and had a suitable donor identified. Treatment with XOSPATA was stopped prior to starting the conditioning regimen for HSCT and could be resumed after transplant in patients meeting appropriate study protocol criteria.²

^‡Only responses prior to HSCT were included in the CR/CRh rate reported in the XOSPATA Prescribing Information.¹

^§Prior AML chemotherapy regimens included standard-dose cytarabine + idarubicin (39%); high-dose cytarabine (27%); standard-dose cytarabine + daunorubicin (26%); azacitidine (7%); decitabine (5%); high-dose cytarabine + daunorubicin (4%); low-dose cytarabine (4%); high-dose cytarabine + idarubicin (3%); standard-dose cytarabine + mitoxantrone (3%); and standard-dose cytarabine + daunorubicin + cladribine (1%); as well as other regimens (44%).²

^||MEC: mitoxantrone 8 mg/m², etoposide 100 mg/m², and cytarabine 1000 mg/m² once daily by IV infusion Days 1 to 5.¹

^¶FLAG-IDA: granulocyte colony-stimulating factor 300 mcg/m² once daily by SC injection Days 1 to 5, fludarabine 30 mg/m² once daily by IV infusion Days 2 through 6, cytarabine 2000 mg/m² once daily by IV infusion Days 2 through 6, idarubicin 10 mg/m² once daily by IV infusion Days 2 through 4.¹

^#LDAC: cytarabine 20 mg twice daily by SC injection or IV infusion for 10 days.¹

**AZA: azacitidine 75 mg/m² once daily by SC injection or IV infusion for 7 days.¹

Admiral trial description

Key Eligibility Criteria^4††

Adult patients with primary AML or AML secondary to myelodysplastic syndrome
Positive for FLT3 mutations (FLT3-ITD, FLT3-TKD-D835, or FLT3-TKD-I836) as determined by the central lab
Refractory to, or relapsed after, first-line AML therapy (with or without HSCT)

Exclusion Criteria^4††

Patients in second or later hematologic relapse or having received salvage therapy for refractory disease
Patients with long QT syndrome at screening
Patients with hypokalemia and hypomagnesemia at screening (defined as values below LLN)

Patients Permitted

Patients with prior HSCT (n=74/371)⁵
Patients who were transfusion dependent (n=294/371)¹
Patients previously treated with midostaurin or sorafenib (n=45/371)^2,4

††Does not include all patient inclusion and exclusion criteria for the ADMIRAL trial.⁴

Transplant was allowed in the ADMIRAL trial²

During the ADMIRAL trial, patients who achieved a response in either treatment arm that allowed them to undergo HSCT^‡‡ based on each institution's assessment—and who had a suitable donor identified—went on to receive transplant during the study.

26^%

of patients in the XOSPATA arm received HSCT (95% CI: 20.2, 31.4; n=63/247)

15^%

of patients in the salvage chemotherapy arm received HSCT (95% CI: 9.5, 22.9; n=19/124)

‡‡Treatment with XOSPATA was stopped prior to starting the conditioning regimen for HSCT. XOSPATA treatment could be resumed after transplant in patients who were between 30 and 90 days post-HSCT, had successful engraftment with ANC ≥500/mm³ and platelets ≥20,000/mm³ without transfusions, did not have Grade ≥2 acute graft-vs-host disease, and were in composite complete remission (CRc).²

The ADMIRAL Trial Included FLT3m+ Patients Eligible for High- or Low-Intensity Chemotherapy¹

Table of baseline patient characteristics in the ADMIRAL Trial.

§§The remaining 5 patients were negative by the diagnostic test.²

||||One patient in the comparator salvage chemotherapy arm had refractory relapse AML at baseline.¹

¶¶The remaining 58 patients included those with cytogenetic risk status that cannot be categorized as intermediate, unfavorable, or favorable.²

##Patients were defined as transfusion dependent at baseline if they were dosed and received any RBC or platelet transfusions within the 56-day baseline period.¹

Results Available in Publication

The complete ADMIRAL trial has been peer-reviewed and published in a medical journal. The efficacy and safety evaluated in the ADMIRAL trial contributed to the clinical body of evidence for XOSPATA.

View XOSPATA Safety

Request a XOSPATA Rep

View XOSPATA Overall Survival Data

AML=acute myeloid leukemia; ANC=absolute neutrophil count; CI=confidence interval; CR=complete remission; CRh=complete remission with partial hematologic recovery; FLT3=FMS-like tyrosine kinase 3; HSCT=hematopoietic stem cell transplant; ITD=internal tandem duplication; IV=intravenous; LDAC=low-dose cytarabine; LLN=lower limit of normal; m+=mutation-positive; OS=overall survival; QT=cardiac ventricular repolarization; RBC=red blood cell; SC=subcutaneous; TKD=tyrosine kinase domain.

References: 1. XOSPATA [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Astellas. XOSPATA. Data on File. 3. Ballesta-López O, Solana-Altabella A, Megías-Vericat JE, Martínez-Cuadrón D, Montesinos P. Gilteritinib use in the treatment of relapsed or refractory acute myeloid leukemia with a FLT3 mutation. Future Oncol (Epub) 09-25-2020. 4. ClinicalTrials.gov. A study of ASP2215 versus salvage chemotherapy in patients with relapsed or refractory acute myeloid leukemia (AML) with FMS-like tyrosine kinase (FLT3) mutation (11-30-2021). https://clinicaltrials.gov/ct2/show/NCT02421939. Accessed 1-19-2022. 5. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med 2019;381(18):1728-40.

Warnings and Precautions

Differentiation Syndrome (See BOXED WARNING) 3% of 319 patients treated with XOSPATA in the clinical trials experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms and other clinical findings of differentiation syndrome in patients treated with XOSPATA included fever, dyspnea, pleural effusion, pericardial effusion, pulmonary edema, hypotension, rapid weight gain, peripheral edema, rash, and renal dysfunction. Some cases had concomitant acute febrile neutrophilic dermatosis. Differentiation syndrome occurred as early as 1 day and up to 82 days after XOSPATA initiation and has been observed with or without concomitant leukocytosis. If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. Taper corticosteroids after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt XOSPATA until signs and symptoms are no longer severe.

Posterior Reversible Encephalopathy Syndrome (PRES) 1% of 319 patients treated with XOSPATA in the clinical trials experienced posterior reversible encephalopathy syndrome (PRES) with symptoms including seizure and altered mental status. Symptoms have resolved after discontinuation of XOSPATA. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue XOSPATA in patients who develop PRES.

Prolonged QT Interval XOSPATA has been associated with prolonged cardiac ventricular repolarization (QT interval). 1% of the 317 patients with a post-baseline QTc measurement on treatment with XOSPATA in the clinical trial were found to have a QTc interval greater than 500 msec and 7% of patients had an increase from baseline QTc greater than 60 msec. Perform electrocardiogram (ECG) prior to initiation of treatment with XOSPATA, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. Interrupt and reduce XOSPATA dosage in patients who have a QTcF >500 msec. Hypokalemia or hypomagnesemia may increase the QT prolongation risk. Correct hypokalemia or hypomagnesemia prior to and during XOSPATA administration.

Pancreatitis 4% of 319 patients treated with XOSPATA in the clinical trials experienced pancreatitis. Evaluate patients who develop signs and symptoms of pancreatitis. Interrupt and reduce the dose of XOSPATA in patients who develop pancreatitis.

Embryo-Fetal Toxicity XOSPATA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with XOSPATA and for 6 months after the last dose of XOSPATA. Advise males with female partners of reproductive potential to use effective contraception during treatment with XOSPATA and for 4 months after the last dose of XOSPATA. Pregnant women, patients becoming pregnant while receiving XOSPATA or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

Adverse Reactions

Fatal adverse reactions occurred in 2% of patients receiving XOSPATA. These were cardiac arrest (1%) and one case each of differentiation syndrome and pancreatitis. The most frequent (≥5%) nonhematological serious adverse reactions reported in patients were fever (13%), dyspnea (9%), renal impairment (8%), transaminase increased (6%) and noninfectious diarrhea (5%).

7% discontinued XOSPATA treatment permanently due to an adverse reaction. The most common (>1%) adverse reactions leading to discontinuation were aspartate aminotransferase increased (2%) and alanine aminotransferase increased (2%).

The most frequent (≥5%) grade ≥3 nonhematological adverse reactions reported in patients were transaminase increased (21%), dyspnea (12%), hypotension (7%), mucositis (7%), myalgia/arthralgia (7%), and fatigue/malaise (6%).

Other clinically significant adverse reactions occurring in ≤10% of patients included: electrocardiogram QT prolonged (9%), hypersensitivity (8%), pancreatitis (5%), cardiac failure (4%), pericardial effusion (4%), acute febrile neutrophilic dermatosis (3%), differentiation syndrome (3%), pericarditis/myocarditis (2%), large intestine perforation (1%), and posterior reversible encephalopathy syndrome (1%).

Lab Abnormalities Shifts to grades 3-4 nonhematologic laboratory abnormalities in XOSPATA treated patients included phosphate decreased (14%), alanine aminotransferase increased (13%), sodium decreased (12%), aspartate aminotransferase increased (10%), calcium decreased (6%), creatine kinase increased (6%), triglycerides increased (6%), creatinine increased (3%), and alkaline phosphatase increased (2%).

Drug Interactions

Combined P-gp and Strong CYP3A Inducers Concomitant use of XOSPATA with a combined P-gp and strong CYP3A inducer decreases XOSPATA exposure which may decrease XOSPATA efficacy. Avoid concomitant use of XOSPATA with combined P-gp and strong CYP3A inducers.

Strong CYP3A inhibitors Concomitant use of XOSPATA with a strong CYP3A inhibitor increases XOSPATA exposure. Consider alternative therapies that are not strong CYP3A inhibitors. If the concomitant use of these inhibitors is considered essential for the care of the patient, monitor patient more frequently for XOSPATA adverse reactions. Interrupt and reduce XOSPATA dosage in patients with serious or life-threatening toxicity.

Drugs that Target 5HT2B Receptor or Sigma Nonspecific Receptor Concomitant use of XOSPATA may reduce the effects of drugs that target the 5HT2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline). Avoid concomitant use of these drugs with XOSPATA unless their use is considered essential for the care of the patient.

P-gp, BCRP, and OCT1 Substrates Based on in vitro data, gilteritinib is a P-gp, breast cancer resistant protein (BCRP), and organic cation transporter 1 (OCT1) inhibitor. Coadministration of gilteritinib may increase the exposure of P-gp, BCRP, and OCT1 substrates, which may increase the incidence and severity of adverse reactions of these substrates. For P-gp, BCRP, or OCT1 substrates where small concentration changes may lead to serious adverse reactions, decrease the dose or modify the dosing frequency of such substrate and monitor for adverse reactions as recommended in the respective prescribing information.

ADMIRAL TRIAL

The ADMIRAL Trial Is a Phase 3 Study of the Only FDA-Approved Treatment in Relapsed or Refractory FLT3m+ AML1-3

ADMIRAL study design1,2

Admiral trial description

Key Eligibility Criteria4††

Exclusion Criteria4††